The long term objective of this proposal is to further the understanding of the cellular mechanisms related to the development and consequence of heroin self-administration. This objective will be accomplished by comparing coordinate changes in multiple mRNA levels from nucleus accumbens (NAcc) following various times (1, 10 and 60 days) of heroin self-administration with vehicle administration. The regional specificity of such changes will be determined by comparing NAcc with dorsal caudate. Changes in the candidate mRNA levels in these regions will also be assessed following food self-administration (1, 10 and 60 days) to determine which effects are specifically related to heroin reinforcement versus those changes attributable to general reinforcement processes. Inasmuch as mu opiate receptors in NAcc are generally considered to mediate opiate reinforcement, it is likely that mu receptors are located on GABAergic medium spiny neurons (MSN), the principal neuronal population within the NAcc. Therefore, it hypothesized that heroin self- administration will induce regionally specific changes in levels of mRNA of proteins associated with opiate reinforcement and GABAergic MSN function. To this end, the following specific aims are proposed: l) Comparison of coordinate changes in multiple candidate mRNAs between the NAcc and dorsal caudate at the tissue level following heroin self- administration 2) Comparison of electrophysiological properties and gene expression profiles of single MSN between NAcc and dorsal caudate following heroin self-administration Expression profiles will be constructed from single MSN using in situ transcription and DNA amplification and will be quantified using slot blot screens containing plasmid cDNAs corresponding to the candidate mRNAs. In the second specific aim, electrophysiological characteristics unique to MSN will be determined prior to in situ transcription. Characterization of alterations in levels of selected mRNAs from MSN is a preliminary step in the elucidation of the molecular mechanisms that underlie opiate reinforcement and addiction.